Outpatient <scp>CD28</scp>‐costimulated <scp>CAR</scp> T‐cells for B‐cell malignancies with <scp>CNS</scp> involvement
Authors: Khaled Sanber, Andrew Ly, Angela Ondo, Kathy Mooney, Julie Baker, Audra Shedeck, Nina Wagner‐Johnston, Tania Jain
Journal: American Journal of Hematology (2023)

There are limited data on the safety of chimeric antigen receptor (CAR) T-cells with the CD28 co-stimulatory domain (CD28 CAR T-cells), such as axicabtagene ciloleucel (Axi-cel) or brexucabtagene autoleucel (Brexu-cel), in patients with active or prior central nervous system (CNS) involvement. Due to concerns over the risk of immune effector cell-associated cytotoxicity (ICANS), patients with CNS disease were largely excluded from the pivotal ZUMA trials that led to the approval of CD28 CAR T-cells for diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and B-cell acute lymphoblastic leukemia (B-ALL).1 Although anecdotal and small retrospective reports have been published,2-6 the safety of CD28 CAR T-cell therapy in patients with CNS involvement has not been adequately evaluated. Furthermore, the safety and feasibility of outpatient administration of CAR T-cells for patients with active or prior CNS involvement remain unclear. Herein, we report on our institutional experience with outpatient CD28 CAR T-cell administration in 10 consecutive patients with CNS involvement. We performed a retrospective analysis of outcomes for all patients who received commercially available CD28 CAR T-cells at Johns Hopkins Hospital between January 2019 and November 2022 for B-cell malignancies with previously treated or active CNS involvement. The study was approved by the Institutional Review Board of Johns Hopkins. Patients were considered to have active CNS disease if they had radiographic evidence of CNS involvement or malignant B-cells detectable by flow cytometry in the cerebrospinal fluid (CSF) at their last assessment prior to CAR T-cell administration. Response to treatment was defined by previously published criteria for lymphoma7 and B-ALL,8 and each patient was reviewed by two investigators (K.S. and T.J.). Cytokine release syndrome (CRS) and ICANS were assessed based on the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading. CRS and ICANS were managed in accordance with the institutional guidelines. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. All statistical analyses were performed using GraphPad Prism (v9.2.0). Patient characteristics, adverse events, and responses are summarized in Figure 1A. The median age at the time of CAR T-cell administration was 55 years (range 33–71). Five patients (50.0%) had DLBCL: one patient with DLBCL had active CNS disease detectable by flow cytometry in the CSF at the time of CAR T-cell administration, and four patients had previously treated CNS disease. One patient (10.0%) had mantle cell lymphoma (MCL) with previously treated secondary CNS involvement. One patient (10.0%) had active primary CNS lymphoma (PCNSL) at the time of CAR T-cell administration. Three patients (30.0%) had B-ALL: one patient with B-ALL had active CNS disease with parenchymal involvement at the time of CAR T-cell administration, and two patients had previously treated CNS disease with negative CSF by flow cytometry. Six patients (60.0%) received axi-cel (five patients with DLBCL and 1 patient with PCNSL) and four patients (40.0%) received brexu-cel (one patient with MCL and three patients with B-ALL). All patients received lymphodepleting chemotherapy with either fludarabine/cyclophosphamide (n = 7, 70%) or bendamustine (n = 3, 30%) when fludarabine was not available due to a national shortage. Seven patients (70.0%) received bridging therapy: 3 received intrathecal chemotherapy, three received high-dose methotrexate, and 1 received polatuzumab plus bendamustine plus rituximab (pola-BR). None received prophylactic steroids. Nine patients (90.0%) were treated in the outpatient setting but were subsequently admitted for management of CAR T-cell-related toxicities, including CRS/ICANS for eight patients and sepsis secondary to Clostridium difficile infection for one patient. The median duration of admission was six days (range 3–33) with one patient requiring a 2-day admission to the intensive care unit (ICU). One patient (10.0%) had a planned admission at the time of CAR T-cell administration to monitor for potential toxicities due to significant comorbidities related to underlying systemic lupus erythromatosus. Nine patients (90.0%) had grade 1–2 CRS and none had grade 3–4 CRS (Figure 1A,B). Eight patients received tocilizumab for CRS. Two patients (20.0%) had grade 1–2 ICANS, and one patient (10.0%) had grade 3 ICANS (Figure 1A,B). One out of three patients with active CNS involvement had ICANS (grade 2; Figure 1A). Two (%) patients received dexamethasone for CRS/ICANS and one of them also received anakinra for grade 3 ICANS). There were no toxicity-related deaths. Overall, six patients (60.0%; 3 DLBCL, 1 PCNSL, and 2 B-ALL) achieved a complete response (CR)/CR with incomplete hematologic recovery (CRi), and four of these patients have ongoing CR/CRi at a follow-up of 83–674 days (Figure 1A). Our study adds to the limited data available for the use of CD28 CAR T-cells in patients with active or previously treated CNS disease and extends that to the outpatient setting. Our outpatient infrastructure, which enables close monitoring and expeditious admission if needed, facilitates the administration of these treatments in an outpatient setting and is currently being explored universally due to the consequent reduction in healthcare costs and greater autonomy it offers to patients. Data on the safety of CD28 CAR T-cells in patients with B-cell malignancies with CNS involvement are mostly limited to small retrospective studies. In these studies, the incidence rates of CRS/ICANS have varied widely: 40%–100% for any grade CRS, 0%–33% for grade 3–4 CRS, 40%–67% for any grade ICANS, and 31%–40% for grade 3–4 ICANS.2-4 Additionally, a small prospective trial of CD28 CAR T-cells in patients with PCNSL reported grade 1–2 CRS and grade 1–2 ICANS in all five patients evaluated (100%).9 Another clinical trial of CD28 CAR T-cells in patients with primary or secondary CNS lymphoma is ongoing.10 Data on the safety of CD28 CAR T-cells in other B-cell malignancies, such as B-ALL and MCL, are even more scarce.6 Additionally, none of these studies evaluated the safety of outpatient administration of CAR T-cells in patients with CNS involvement. Relapsed/refractory primary and secondary CNS lymphoma, as well as B-ALL with CNS involvement, are associated with poor prognoses. Our study, along with others in the series above, indicates that CAR T-cells can offer a feasible treatment option in these settings. The incidence rates of CRS and ICANS in our study were comparable to those reported in the pivotal ZUMA trials. Additionally, these toxicities were manageable using tocilizumab with or without steroids, and there were no toxicity-related deaths. Even though all patients required hospitalization, the duration of hospitalization was relatively limited with a median duration of 6 days. Although only three patients had active CNS disease, we did not observe excessive neurotoxicity in this subgroup of patients. Thus, our data indicate that the presence of CNS disease itself should not preclude treatment with CD28 CAR T cells. We also observed encouraging responses systemically and in the CNS, although larger studies focusing on specific B-cell malignancies with longer follow-up are needed to further evaluate efficacy outcomes. We acknowledge the limitations of our study, including its retrospective nature, limited sample size, and heterogeneity of underlying diagnoses. However, this is the first study, to our knowledge, evaluating the safety of outpatient CD28 CAR T-cells in patients with CNS disease. Overall, our findings support further investigation of the outpatient administration of CD28 CAR T-cells in patients with CNS involvement and argue for the inclusion of these patients in future CAR T-cell clinical trials. While this approach is broadly feasible, it requires significant planning and infrastructure, including 24-hour triage capacity as well as the potential for direct admission of patients to bypass the wait times associated with emergency department visits. Further studies are also warranted to identify preventative strategies that can minimize hospitalization and healthcare costs associated with it. Khaled Sanber designed the study, collected clinical data, performed statistical analysis, interpreted the data, wrote the manuscript, and approved the final draft; Andrew Ly designed the study, collected clinical data, reviewed the manuscript, and approved the final draft; Angela Ondo, Kathy Mooney, Julie Baker, Audra Shedeck, and Nina Wagner-Johnston collected data, reviewed the manuscript, and approved the final draft; Tania Jain designed the study, interpreted the data, reviewed the manuscript, approved the final draft, and supervised the project. None. Tania Jain reports institutional research support from CTI Biopharma, Kartos Therapeutics, Incyte, and Advisory board participation with Care Dx, Bristol Myers Squibb, Incyte, Abbvie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, and Telios Pharma. The data that support the findings of this study are available from the corresponding author upon reasonable request.